The cyclooxygenase (COX) system includes a ubiquitous set of enzymes that are present throughout the human body and that initiate the biochemical conversion of arachidonic acid into various physiologically active metabolites, including various prostaglandins.1 These metabolites can increase or decrease immune function, increase or decrease the propensity of blood to clot, vasodilate blood vessels or vasoconstrict the vessels. They also protect the lining of the gastrointestinal (GI) tract against ulceration.
One of the prostaglandins (prostaglandin E) also affects renal (kidney) function. It decreases renal tubular absorption of sodium, thereby increasing sodium excretion; inadequate sodium excretion causes fluid retention, and thereby causes hypertension (high blood pressure).2 Thus, anything that decreases prostaglandin E production can be expected to increase blood pressure.
Whenever the body suffers an injury, the COX system increases the production of inflammatory metabolites, including prostaglandin E. The increased levels of prostaglandin E then stimulate immune function and inflammation.3 As a result of these effects, prostaglandin E causes and increases the amount of pain a patient experiences following externally induced injuries such as broken bones, or internally induced injuries such as headaches. It also causes pain in chronic conditions such as arthritis.
In light of the importance of the prostaglandins in the generation of pain, a number of analgesic drugs have been developed over the years to block the production of prostaglandin E, and thereby to decrease the amount of pain the patient experiences. These analgesic drugs, that work by primarily blocking the COX enzyme system, are referred to as NSAIDs.
NSAIDs that block both the COX-1 and COX-2 enzymes are often referred to generally as non-selective NSAIDs. NSAIDs that block preferentially the COX-2 enzyme are referred to generally as COX-2 inhibitors.
The Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp 1308-1309 provides well known examples of NSAIDs4. The term NSAIDs includes, but is not limited to, the group consisting of salicylates, indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen, ketoprofen, meclofenamic acid, mefenamic acid, niflumic acid, phenacetin, salidifamides, sulindac, suprofen and tolmetin. The salicylates may include acetylsalicylic acid, sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylic acid, and sodium salicylate.
These analgesics are the most widely consumed pharmaceuticals in the U.S. Although most patients take them for only brief durations of time while treating conditions such as headache or muscle pains, other patients with chronic diseases, such as arthritis, remain on them for months or years.
The non-selective NSAIDs approved by the Food and Drug Administration (FDA) for marketing include indomethacin, ibuprofen, naproxen, etodolac, nabumetone, diclofenac, ketoprofen, and piroxicam. FDA approved COX-2 inhibitors have included valdecoxib, rofecoxib, and celecoxib. All of these NSAIDs have been documented to be extremely effective in reducing pain. However, as a result of their inhibition of the synthesis of prostaglandins, NSAIDs can cause multiple serious problems (adverse reactions).
The most widely recognized problem resulting from NSAIDs that block the COX enzyme system is GI ulcerations. The FDA has estimated that between 10,000 and 20,000 patients in the U.S. per year die from complications resulting from GI ulcerations resulting from these drugs.5 To prevent these GI ulcerations, physicians have prescribed a number of anti-ulcer medications. These include antacids, proton pump inhibitors, and histamine H2-receptor (H-2) blockers.
A subset of the NSAID family, the COX-2 inhibitors, was developed in the hopes that they would be less likely to result in GI ulcerations. The COX-2 inhibitors were developed to block only one of the COX enzymes: the COX-2 enzyme. The COX-2 inhibitors do not block the COX-1 enzyme. Since the COX-1 enzyme is present in the lining of the GI tract, but the COX-2 enzyme is not, it was anticipated that a drug that selectively blocks the COX-2 enzyme would result in less GI toxicity while still alleviating pain. This was found to be the case and thus, beginning in the late 1990s, FDA approved a number of selective COX-2 inhibitors for marketing in the U.S. including rofecoxib, valdecoxib, and celecoxib. Other COX-2 inhibitors include, but are not limited to paracoxib, etoricoxib, and lumiracoxib.
Recently, the potential for NSAIDs, including COX-2 inhibitors, to be associated with severe cardiovascular problems has been recognized. This recognition has led to the drug rofecoxib being removed from the market and to the FDA requiring a boxed warning—boxed warnings are FDA's strongest warnings contained within a drug's labeling—for all NSAIDs, including COX-2 inhibitors. This boxed warning informs physicians that these drugs may cause myocardial infarctions (heart attacks), and other cardiovascular complications.
The FDA summarized its position on the risks to the cardiovascular system from NSAIDs, including COX-2 inhibitors, in a memorandum from John Jenkins and Paul Seligman through Steve Go son (the FDA's Acting Director for the Center for Drug Evaluation and Research) to the New Drug Application files for the various drugs at issue.6 Currently, the FDA has taken the position that it does not know the etiology by which NSAIDs, including COX-2 inhibitors, increase the risk for myocardial infarctions and other cardiovascular complications. The FDA has noted that the increased rate of myocardial infarctions among patients taking NSAIDs, including COX-2 inhibitors, does not occur until the patients have been receiving the drugs for many months. The FDA has also stated that it is unable to discern any difference in risk among the various approved NSAIDs, including COX-2 inhibitors.
A meta-analysis of randomized clinical trials of various NSAIDs has documented that these drugs increase blood pressure.7 The amount of the increase reported in this meta-analysis varied slightly depending upon the specific NSAID (no COX-2 inhibitors were reviewed in this meta-analysis). Overall, the increase in mean blood pressure was 5.0 mm Hg. This level of hypertension is significantly less than that seen in essential hypertension—essential hypertension is the common form of hypertension that occurs for no known reason—but still represents a potential health risk. For example, an increase in mean blood pressure of only 5.0 mm Hg may not seem excessive, but it has been reported that such an increase, even when over a less than chronic period of time, increased the risk of stroke by 67% and of cardiac disease by 15%.8 To that end, prevention of NSAID-induced hypertension can be expected potentially to have major benefits to the health of the millions of Americans who take these medications.
This increased risk of hypertension among patients taking various NSAIDs includes the COX-2 inhibitors. Specifically, the FDA approved drug labeling for the COX-2 inhibitor rofecoxib listed high blood pressure as occurring more frequently in rofecoxib treated patients than in placebo control patients. It should be noted that the FDA approved drug labeling for celecoxib also describes an increased rate of hypertension in patients receiving the drug.
The hypertension resulting from NSAIDs can be expected to affect other parts of the cardiorenal system. These other effects would include edema formation and potentially congestive heart failure. It is thus not surprising that a recent epidemiology study conducted using the United Kingdom's General Practice Research Database documented that patients started on NSAIDs had a 1.6 relative risk (a 60% increased risk compared to patients not receiving the drugs) of being diagnosed with clinical heart failure compared to patients of the same age not started on such drugs.9 
To summarize, clinical data have indicated that the use of NSAIDs, including COX-2 inhibitors, are associated with hypertension, myocardial infarctions, and death. However, to date, no effective mechanism for prophylactically addressing these etiologies has been developed.
CNS stimulants have been utilized for decades to treat primarily two conditions: obesity and ADHD. These drugs increase CNS activity.
Stimulants, also referred to as sympathomimetics, include but are not limited to phentermine, diethylpropion, methamphetamine, dextroamphetamine, methylphenidate, lisdexamphetamine, modafinil, pemoline, dexmethylphenidate, phendimetrazine, benzphetamine, and their salts and prodrugs.
Among the areas of the brain stimulated by CNS stimulants are the brain's satiety center. As a result, CNS stimulants reduce appetite. As a result of the decreased appetite, varying amounts of weight loss occur while patients are on these therapies.10 
Being overweight as well as suffering outright obesity increase the risk of multiple medical conditions. Thus, weight loss is a highly desirable outcome. Unfortunately, weight loss is difficult to achieve without medical or surgical intervention. Medical intervention includes the use of CNS stimulants that reduce appetite.
The FDA has approved CNS stimulants for weight loss. These include phentermine and simbutramine. Both of these agents, while effective in assisting in weight loss, possess serious cardiovascular adverse effects that are included in the drug labeling warnings and will be discussed in greater detail later.
ADHD is a psychiatric diagnosis listed in the Diagnostic and Statistics Manual IV. It includes an increased level of activity in the patient. This increased level of activity impairs the patient's ability to conduct normal daily functions. Such functions can include employment duties and schooling requirements. To that end, it can interfere with the ability to lead a normal productive life.
CNS stimulants improve behavior in patients suffering from ADHD.11,12 This improvement results in enhanced performance in a number of situations including school performance and job performance.
A number of CNS stimulants have been approved by the FDA for the treatment of ADHD and other disorders. These drugs include methylphenidate, d-methylphenidate, amphetamine, dextroamphetamine, and mondafinil.
Although CNS stimulants have been documented to be effective in treating ADHD and in causing weight loss, they do possess significant side effects: including cardiovascular side effects.13 These cardiovascular side effects have resulted in bolded warnings in the labeling of the CNS stimulants.
The hypertensive effect of CNS stimulants has been well recognized in both adults and children.14,15,16,17 These publications document a 3 to 7 torr increase in systolic blood pressure while on stimulant therapy. They also document a statistically significant increase in heart rate: 2 to 8 bpm. The combination of an increased cardiac rate plus an increase in blood pressure results in a significant increase in the cardiac workload.
The increase in blood pressure and cardiac rate with CNS stimulants appears to have clinical significance as evidenced by an increased rate of hospitalizations for cardiac problems17 and an increased risk of sudden death13. To that end, these data and analyses indicate an unmet need for a safer drug product for the treatment of ADHD. Some CNS stimulants have been removed from the market due to the cardiovascular risks they have been found to possess. These include fenfluramine and dexfenfluramine.